Abstract Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that remains progressive and life-limiting despite numerous approved vasodilator therapies. Right ventricular (RV) failure is the ultimate determinant of outcome in PAH and in pulmonary hypertension from more common heart and lung diseases, but there are no approved treatments for RV failure. PAH is more common in women, yet women have better RV function and survival as compared to men with PAH. We and others have shown that lower levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester increase the risk of PAH in men and women and that lower levels are associated with more severe pulmonary vascular disease, worse RV function, and mortality in PAH independent of other sex hormones including estrogen. DHEA has direct effects on nitric oxide (NO) and endothelin-1 (ET-1) synthesis and signaling, two major pathobiologic drivers and therapeutic targets in PAH, and direct antihypertrophic effects on cardiomyocytes. Our long-range goal is to pursue DHEA as a therapeutic intervention in PAH and RV failure in order to provide precision PAH treatment based on sex or sex hormone milieu. This proposal will test the impact of DHEA on RV phenotype and provide critical mechanistic insights into sexual dimorphism in PAH at the level of the pulmonary vasculature, the RV and in the context of major established treatment targets in PAH. A proof of concept randomized double-blind placebo controlled crossover trial to study DHEA treatment in men (n = 13) and women (n = 13) with PAH is planned. In our first aim, we will determine whether DHEA 50 mg daily for 18 weeks affects RV longitudinal strain measured by cardiac magnetic resonance imaging and markers of maladaptive RV hypertrophy and remodeling. We will also assess the impact of DHEA on downstream hormone levels, other PAH intermediate end points, side effects and safety. Second, we will determine whether active treatment with DHEA affects NO and ET-1 biosynthesis in PAH patients. Third, we will determine whether DHEA enhances NO production and attenuates ET-1 synthesis in pulmonary artery endothelial cells isolated from PAH patients. This work will be the first clinical trial of an endogenous sex hormone in PAH and will provide mechanistic insight into sex-based differences in cardiopulmonary phenotypes, leading to a larger parallel arm Phase II trial of DHEA as a novel RV therapeutic.